Project Summary The Oklahoma ACE (OACE) strives to understand the biology of autoimmune diseases through interdisciplinary, collaborative research that integrates clinical and basic questions. This prior ACE work has led to 128 publications, including 42 with authors from 2 or more ACEs, leadership of a previous and ongoing ACE clinical trial and lead or near lead recruitment in three ACE trials while a Basic ACE. We build on this expertise through this UM1 Clinical ACE submission. Although significant progress in unveiling mechanisms of autoimmune disease pathogenesis has been made, development of targeted therapies is critically lacking. For autoimmune disease therapeutic development to succeed and patient outcomes to improve, deepened understanding of molecular disease heterogeneity, therapeutic pharmacobiology and improved trial designs are needed. The Oklahoma ACE will pursue a novel, comprehensive theme of accelerating discovery and translation by deconstructing molecular heterogeneity to enrich for patients with common molecular pathways, partnered with repurposed therapies from other fields and novel trial designs which eliminate confounding background polypharmacy, to address these unmet needs. Our primary clinical project utilizes our innovative SLE trial design which uses serial depomedrol injections to suppress disease, halting of background immunosuppressive drugs to provide a more pristine environment to test the effectiveness of mycophenolate mofetil with or without add-on of tacrolimus to suppress SLE activity. Partnered mechanistic studies will test our soluble mediator flare index and other select activated immune cell subsets for the ability to predict upcoming flare, as well as to test specific hypotheses of MMF response/resistance and of SLE disease flare mechanisms. Preliminary data in our alternate clinical project has found critical roles of neutrophils in neuromyelitis optica, a complex autoimmune disease where up to 40% of patients have continual relapse and damage even with treatment with B cell depleting therapies and steroids. Pre-clinical work from this team has shown efficacy in two animal models of alpha-1 anti-trypsin, which inhibits neutrophil elastase. This first-in-NMO study will assess effectiveness and safety, as well as mechanistic studies which test biologic mechanisms of treatment, predictors of response and molecular mechanisms of NMO flare. Our collaborative project deconstructs molecular heterogeneity and associated pathogenic mechanisms of disease in subgroups of SLE patients. Building on preliminary data which identifies seven molecular subsets by gene expression profiling, soluble mediators and autoantibodies, proposed studies will test hypotheses of specific molecular mechanisms through deep immunophenotyping and single cell technologies such as scRNAseq, CITE-seq, CyTOF and ChipCytometry. These projects, facilitated by our Admin Core, will study fundamental aspects of autoimmunity and conduct focused clinical trials for SLE, NMO and other autoimmune diseases. Our Center will also continue to collaborate and recruit for the ACE Network.